It's Not Always the DNA

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Newswise Damage to DNA is an issue for all cells, particularly in cancer, where the mechanisms that repair damage typically fail. The same agents that damage DNA also damage its sister molecule messenger RNA (mRNA), which ferries transcripts of the genes to the tens of thousands of ribosomes in each cell. But little attention has been paid to this damage.

Everybody thought, Why care about the messenger RNA? These molecules have high turnover rates and are quickly degraded, so what does it matter if one is damaged? said Hani Zaher, PhD, assistant professor of biology in Arts & Sciences at Washington University in St. Louis.

In organisms like E. coli or yeast, thats probably true, Zaher said. You dont have to worry about mRNA because it turns over really fast. But in neurons you cant use that argument because an mRNA can persist, in some cases for days. And if that mRNA is really damaged it can become a big problem.

There may be cases where messenger RNA is just as important as DNA, said Carrie Simms, PhD, a postdoctoral associate in Zahers lab. Clearly oxidative damage to RNA is somehow involved in neurodegenerative diseases, such as Alzheimers and ALS. Its not necessarily causing the disease; it may just be some sort of byproduct; but its in the mix.

Under normal conditions only about 1 percent of the cellular mRNAs are oxidized, Zaher said, but if you have oxidative stress, for whatever reason, a higher percentage can be damaged.

One of the hallmarks of Alzheimers is oxidative stress, and studies have shown that in people with advanced Alzheimers, half of the RNA molecules in the neurons may be oxidized.

In the November 13 issue of Cell Reports, Zaher, Simms and their colleagues report that when they fed oxidized mRNA to ribosomes, the nanomachines that convert mRNA to protein, the ribosomes jammed and stopped.

A stuck ribosome could be rescued by factors that released it from the mRNA and chewed up the damaged transcipt. But if the factors involved in this quality-control system were absent, damaged mRNA accumulated in the cell, just as it does in Alzheimers.

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It's Not Always the DNA